Lifespan in the nematode, Caenorhabditis elegans, is determined by genetic pathways and by environmental conditions. One of the most dramatic genetic effects on longevity is observed in animals with mutations inactivating the nematode's insulin-like signaling pathway. In particular, defects in the DAF-2/insulin-like pathway can triple the adult lifespan. Previous studies showed that DAF-2/insulin signaling affects lifespan non-cell autonomously from different cells in the body. Using a transgenic approach, we have found that cells throughout the nervous system have the capability of promoting normal lifespan through the DAF-2/insulin pathway. This finding suggests that a DAF-2/insulin signaling produces a diffusible signal that coordinates aging in the body. We are currently conducting genetic screens, using RNA-interference, to identify genes involved in the production and reception of this diffusible signal. A second focus of this work is to study how DAF-2/insulin signaling affects metabolism in C. elegans. In humans, insulin is an important controller of metabolism and health, as cellular insulin resistance is a hallmark of type II diabetes. Therefore, we are working to identify how the DAF-2 pathway interacts with known metabolic control pathways, including the TOR kinase pathway that senses nutrient availability. These studies may reveal ways to modify cellular insulin sensitivity. In addition, we are characterizing how mitochondrial function is altered in animals with defective DAF-2/insulin signaling. Ultimately, we hope to understand the metabolic changes that promote long lifespan in daf-2 pathway mutants.